Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside.

ConspectusMolecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody.This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq-antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed.The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t1/2 ∼ 110 min) or gallium-68 (t1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4-24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.

Tumor targeted alpha particle therapy with an actinium-225 labelled antibody for carbonic anhydrase IX.

Selective antibody targeted delivery of α particle emitting actinium-225 to tumors has significant therapeutic potential. This work highlights the design and synthesis of a new bifunctional macrocyclic diazacrown ether chelator, H2MacropaSqOEt, that can be conjugated to antibodies and forms stable complexes with actinium-225. The macrocyclic diazacrown ether chelator incorporates a linker comprised of a short polyethylene glycol fragment and a squaramide ester that allows selective reaction with lysine residues on antibodies to form stable vinylogous amide linkages. This new H2MacropaSqOEt chelator was used to modify a monoclonal antibody, girentuximab (hG250), that binds to carbonic anhydrase IX, an enzyme that is overexpressed on the surface of cancers such as clear cell renal cell carcinoma. This new antibody conjugate (H2MacropaSq-hG250) had an average chelator to antibody ratio of 4 : 1 and retained high affinity for carbonic anhydrase IX. H2MacropaSq-hG250 was radiolabeled quantitatively with [225Ac]AcIII within one minute at room temperature with micromolar concentrations of antibody and the radioactive complex is stable in human serum for >7 days. Evaluation of [225Ac]Ac(MacropaSq-hG250) in a mouse xenograft model, that overexpresses carbonic anhydrase IX, demonstrated a highly significant therapeutic response. It is likely that H2MacropaSqOEt could be used to modify other antibodies providing a readily adaptable platform for other actinium-225 based therapeutics.

Update on Total Pancreatectomy With Islet Autotransplantation.

Total pancreatectomy with islet autotransplantation is a therapeutic option to effectively achieve pain relief and improvements in quality of life for selected patients with debilitating pain from chronic pancreatitis. The understanding of the best application and clinical execution of this procedure is in evolution, with outcomes studies and clinical trials in progress.

Theranostic Nuclear Medicine with Gallium-68, Lutetium-177, Copper-64/67, Actinium-225, and Lead-212/203 Radionuclides.

Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or ß+-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, ß-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain ß+-emitting gallium-68 and ß-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.

Pre-targeting amyloid-ß with antibodies for potential molecular imaging of Alzheimer's disease.

With the aim of developing the concept of pretargeted click chemistry for the diagnosis of Alzheimer's disease two antibodies specific for amyloid-ß were modified to incorporate trans-cyclooctene functional groups. Two bis(thiosemicarbazone) compounds with pendant 1,2,4,5-tetrazine functional groups were prepared and radiolabelled with positron emitting copper-64. The new copper-64 complexes rapidly react with the trans-cyclooctene functionalized antibodies in a bioorthogonal click reaction and cross the blood-brain barrier in mice.

Stem Cell Therapy Improves Human Islet Graft Survival in Mice via Regulation of Macrophages.

Islet/ß-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-γ-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets cotransplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance ß-cell survival during islet/ß-cell transplantation for the treatment of type 1 diabetes or other diseases.

Distal Pancreatectomy for Pancreatitis in the Modern Era.

INTRODUCTION: Distal pancreatectomy has not been well examined in the modern era to guide management for pancreatitis. We evaluated this heterogeneous group and the preoperative factors associated with clinically relevant postoperative pancreatic fistula (CR-POPF). METHODS: Patients undergoing distal pancreatectomy at a single academic institution from August 2012 to January 2020 were evaluated. Univariate and multivariate logistic regressions were conducted between preoperative factors and CR-POPF. RESULTS: One hundred and thirty patients underwent distal pancreatectomy. Indication for operative management included chronic pancreatitis and/or pseudotumor in 24.6% (n = 32), disconnected left pancreatic remnant in 31.5% (n = 41), chronic distal pseudocyst in 20.8% (n = 27), and distal necrosis in 13.8% (n = 18). Significant complications (Clavien-Dindo grade ≥ III) were seen in 34% of patients. After surgery, 34.2% developed diabetes, 40% had persistent opioid use, and 22.3% had CR-POPF. In multivariate analysis, male sex was significantly associated with CR-POPF (odds ratio 3.1, P = 0.037), and having a preoperative, therapeutic endoscopic retrograde cholangiopancreatography was protective (odds ratio 0.28, P = 0.020). CONCLUSIONS: Distal pancreatectomy is undertaken in pancreatitis with high morbidity. Female sex and preoperative, therapeutic endoscopic retrograde cholangiopancreatography were significant protective factors for CR-POPF. The natural history of this approach is relevant for those with distal pancreatitis failing medical management.

The Association of Smoking and Alcohol Abuse on Anxiety and Depression in Patients With Recurrent Acute or Chronic Pancreatitis Undergoing Total Pancreatectomy and Islet Autotransplantation: A Report From the Prospective Observational Study of TPIAT Cohort.

OBJECTIVES: Smoking and alcohol use are risk factors for acute and chronic pancreatitis, and their role on anxiety, depression, and opioid use in patients who undergo total pancreatectomy and islet autotransplantation (TPIAT) is unknown. METHODS: We included adults enrolled in the Prospective Observational Study of TPIAT (POST). Measured variables included smoking (never, former, current) and alcohol abuse or dependency history (yes vs no). Using univariable and multivariable analyses, we investigated the association of smoking and alcohol dependency history with anxiety and depression, opioid use, and postsurgical outcomes. RESULTS: Of 195 adults studied, 25 were current smokers and 77 former smokers, whereas 18 had a history of alcohol dependency (of whom 10 were current smokers). A diagnosis of anxiety was associated with current smoking (P = 0.005), and depression was associated with history of alcohol abuse/dependency (P = 0.0001). However, active symptoms of anxiety and depression at the time of TPIAT were not associated with smoking or alcohol status. Opioid use in the past 14 days was associated with being a former smoker (P = 0.005). CONCLUSIONS: Active smoking and alcohol abuse history were associated with a diagnosis of anxiety and depression, respectively; however, at the time of TPIAT, symptom scores suggested that they were being addressed.

Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = -0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

A Mouse Model for Chronic Pancreatitis via Bile Duct TNBS Infusion.

Chronic pancreatitis (CP) is a complex disease involving pancreatic inflammation and fibrosis, glandular atrophy, abdominal pain and other symptoms. Several rodent models have been developed to study CP, of which the bile duct 2,4,6 -trinitrobenzene sulfonic acid (TNBS) infusion model replicates the features of neuropathic pain seen in CP. However, bile duct drug infusion in mice is technically challenging. This protocol demonstrates the procedure of bile duct TNBS infusion for generation of a CP mouse model. TNBS was infused into the pancreas through the ampulla of Vater in the duodenum. This protocol optimized drug volume, surgical techniques, and drug handling during the procedure. TNBS-treated mice showed features of CP as reflected by bodyweight and pancreas weight reductions, changes in pain-associated behaviors, and abnormal pancreatic morphology. With these improvements, mortality associated with TNBS injection was minimal. This procedure is not only critical in generating pancreatic disease models but is also useful in local pancreatic drug delivery.

Travel distance and overall survival in hepatocellular cancer care.

BACKGROUND: Our objective was to assess the relationship between overall survival (OS) and distance travelled to the treating facility for patients undergoing liver resection for hepatocellular carcinoma and to determine whether this relationship was dependent upon the structural factors of the treating facility. METHODS: Using National Cancer Database, we focused on extremes of travel: Local (<12.5 miles to treating facility) and Travel (≥50 miles). We analyzed OS with Cox models; we estimated stratified models to assess interaction between distance and facility characteristics (volume, academic status). RESULTS: We included 6860 patients. After correction for confounding, distance travelled was not associated with OS (p = 0.444). However, Travel patients treated at high-volume, academic centers had worse OS compared to Local patients (HR 1.54, 95%CI 1.07-2.21); this association was not seen for patients treated at low volume, academic centers (p = 0.708) high volume non-academic centers (p = 0.174) or low volume non-academic centers (p = 515). CONCLUSION: For those patients treated at high-volume, academic centers, living far from the facility was associated with worse OS. The reasons for this association should be investigated further.

Travel distance and its interaction with patient and hospital factors in pancreas cancer care.

BACKGROUND: Although volume-outcome literature supports regionalization for complex procedures, travel may be burdensome. We assessed the relationship between overall survival and travel distance for patients undergoing pancreatic resection for adenocarcinoma. METHODS: We analyzed the Fall 2018 National Cancer Database Public Use File. We defined distance traveled as a categorical variable (<12.5 miles, 12.5-50mi, and >50mi). We analyzed overall survival (OS) as a function of distance traveled using the log rank test and Cox proportional hazards models; we estimated stratified models to assess for interaction between distance and other relevant covariates. RESULTS: In adjusted analysis of 39,089 patients, greater distance was associated with decreased OS (p = 0.0029). We found interactions between distance and center type, comorbidities, and age. Distance traveled was a negative factor for patients treated at low-volume academic centers (but not high-volume academic or non-academic centers). Additionally, distance traveled was a negative factor for OS in young, healthy patients but not geriatric, ill patients. CONCLUSION: Traveling more than 12.5 miles for pancreatic resection was associated with worse OS. Prior to regionalization, evaluation of local resources may be necessary.

Islet autotransplantation improves glycemic control in patients undergoing elective distal pancreatectomy for benign inflammatory disease.

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.

American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis.

DESCRIPTION: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update is to review the available evidence and expert recommendations regarding the clinical care of patients with pancreatic necrosis and to offer concise best practice advice for the optimal management of patients with this highly morbid condition. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. This review is framed around the 15 best practice advice points agreed upon by the authors, which reflect landmark and recent published articles in this field. This expert review also reflects the experiences of the authors, who are advanced endoscopists or hepatopancreatobiliary surgeons with extensive experience in managing and teaching others to care for patients with pancreatic necrosis. BEST PRACTICE ADVICE 1: Pancreatic necrosis is associated with substantial morbidity and mortality and optimal management requires a multidisciplinary approach, including gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition. In situations where clinical expertise may be limited, consideration should be given to transferring patients with significant pancreatic necrosis to an appropriate tertiary-care center. BEST PRACTICE ADVICE 2: Antimicrobial therapy is best indicated for culture-proven infection in pancreatic necrosis or when infection is strongly suspected (ie, gas in the collection, bacteremia, sepsis, or clinical deterioration). Routine use of prophylactic antibiotics to prevent infection of sterile necrosis is not recommended. BEST PRACTICE ADVICE 3: When infected necrosis is suspected, broad-spectrum intravenous antibiotics with ability to penetrate pancreatic necrosis should be favored (eg, carbapenems, quinolones, and metronidazole). Routine use of antifungal agents is not recommended. Computed tomography-guided fine-needle aspiration for Gram stain and cultures is unnecessary in the majority of cases. BEST PRACTICE ADVICE 4: In patients with pancreatic necrosis, enteral feeding should be initiated early to decrease the risk of infected necrosis. A trial of oral nutrition is recommended immediately in patients in whom there is absence of nausea and vomiting and no signs of severe ileus or gastrointestinal luminal obstruction. When oral nutrition is not feasible, enteral nutrition by either nasogastric/duodenal or nasojejunal tube should be initiated as soon as possible. Total parenteral nutrition should be considered only in cases where oral or enteral feeds are not feasible or tolerated. BEST PRACTICE ADVICE 5: Drainage and/or debridement of pancreatic necrosis is indicated in patients with infected necrosis. Drainage and/or debridement may be required in patients with sterile pancreatic necrosis and persistent unwellness marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications, including gastrointestinal luminal obstruction; biliary obstruction; recurrent acute pancreatitis; fistulas; or persistent systemic inflammatory response syndrome. BEST PRACTICE ADVICE 6: Pancreatic debridement should be avoided in the early, acute period (first 2 weeks), as it has been associated with increased morbidity and mortality. Debridement should be optimally delayed for 4 weeks and performed earlier only when there is an organized collection and a strong indication. BEST PRACTICE ADVICE 7: Percutaneous drainage and transmural endoscopic drainage are both appropriate first-line, nonsurgical approaches in managing patients with walled-off pancreatic necrosis (WON). Endoscopic therapy through transmural drainage of WON may be preferred, as it avoids the risk of forming a pancreatocutaneous fistula. BEST PRACTICE ADVICE 8: Percutaneous drainage of pancreatic necrosis should be considered in patients with infected or symptomatic necrotic collections in the early, acute period (<2 weeks), and in those with WON who are too ill to undergo endoscopic or surgical intervention. Percutaneous drainage should be strongly considered as an adjunct to endoscopic drainage for WON with deep extension into the paracolic gutters and pelvis or for salvage therapy after endoscopic or surgical debridement with residual necrosis burden. BEST PRACTICE ADVICE 9: Self-expanding metal stents in the form of lumen-apposing metal stents appear to be superior to plastic stents for endoscopic transmural drainage of necrosis. BEST PRACTICE ADVICE 10: The use of direct endoscopic necrosectomy should be reserved for those patients with limited necrosis who do not adequately respond to endoscopic transmural drainage using large-bore, self-expanding metal stents/lumen-apposing metal stents alone or plastic stents combined with irrigation. Direct endoscopic necrosectomy is a therapeutic option in patients with large amounts of infected necrosis, but should be performed at referral centers with the necessary endoscopic expertise and interventional radiology and surgical backup. BEST PRACTICE ADVICE 11: Minimally invasive operative approaches to the debridement of acute necrotizing pancreatitis are preferred to open surgical necrosectomy when possible, given lower morbidity. BEST PRACTICE ADVICE 12: Multiple minimally invasive surgical techniques are feasible and effective, including videoscopic-assisted retroperitoneal debridement, laparoscopic transgastric debridement, and open transgastric debridement. Selection of approach is best determined by pattern of disease, physiology of the patient, experience and expertise of the multidisciplinary team, and available resources. BEST PRACTICE ADVICE 13: Open operative debridement maintains a role in the modern management of acute necrotizing pancreatitis in cases not amenable to less invasive endoscopic and/or surgical procedures. BEST PRACTICE ADVICE 14: For patients with disconnected left pancreatic remnant after acute necrotizing mid-body necrosis, definitive surgical management with distal pancreatectomy should be undertaken in patients with reasonable operative candidacy. Insufficient evidence exists to support the management of the disconnected left pancreatic remnant with long-term transenteric endoscopic stenting. BEST PRACTICE ADVICE 15: A step-up approach consisting of percutaneous drainage or endoscopic transmural drainage using either plastic stents and irrigation or self-expanding metal stents/lumen-apposing metal stents alone, followed by direct endoscopic necrosectomy, and then surgical debridement is reasonable, although approaches may vary based on the available clinical expertise.

Islet Harvest in Carbon Monoxide-Saturated Medium for Chronic Pancreatitis Patients Undergoing Islet Autotransplantation.

Stresses encountered during human islet isolation lead to unavoidable ß-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, ß-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less ß-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.

A Study on the Effect of Patient Characteristics, Geographical Utilization, and Patient Outcomes for Total Pancreatectomy Alone and Total Pancreatectomy With Islet Autotransplantation in Patients With Pancreatitis in the United States.

OBJECTIVES: A selective therapy for pancreatitis is total pancreatectomy and islet autotransplantation. Outcomes and geographical variability of patients who had total pancreatectomy (TP) alone or total pancreatectomy with islet autotransplantation (TPIAT) were assessed. METHODS: Data were obtained from the Healthcare Cost and Utilization Project National Inpatient Sample database. Weighed univariate and multivariate analyses were performed to determine the effect of measured variables on outcomes. RESULTS: Between 2002 and 2013, there were 1006 TP and 825 TPIAT in patients with a diagnosis of chronic pancreatitis, and 1705 TP and 830 TPIAT for any diagnosis of pancreatitis. The majority of the TP and TPIAT were performed in larger urban hospitals. Costs were similar for TP and TPIAT for chronic pancreatitis but were lower for TPIAT compared with TP for any type of pancreatitis. The trend for TP and TPIAT was significant in all geographical areas during the study period. CONCLUSIONS: There is an increasing trend of both TP and TPIAT. Certain groups are more likely to be offered TPIAT compared with TP alone. More data are needed to understand disparities and barriers to TPIAT, and long-term outcomes of TPIAT such as pain control and glucose intolerance need further study.

The Impact of Endoscopic Retrograde Cholangiopancreatography on Islet Cell Yield During Total Pancreatectomy With Islet Autotransplantation.

OBJECTIVES: Many patients with recurrent acute and chronic pancreatitis who are candidates for total pancreatectomy and islet cell autotransplantation (TPIAT) undergo endoscopic retrograde cholangiopancreatography (ERCP). However, little is known on the impact of ERCP on TPIAT outcomes. We aimed to explore the effect of antecedent ERCP on islet yield and postoperative insulin requirement after TPIAT. METHODS: Through a prospectively maintained database, we identified patients who underwent TPIAT at our institution between 2009 and 2016. After adjusting for confounders, islet cell yield and postoperative insulin requirement were compared between subjects who did and did not undergo ERCP within 2 years prior to TPIAT. RESULTS: Data were available on 167 TPIAT patients during the study period; 105 (62.9%) had undergone ERCP within 2 years prior. Prior ERCP was not associated with a reduction in islet equivalents per patient kilogram (odds ratio, 1.37; 95% confidence interval, 0.75-2.5; P = 0.31). Antecedent ERCP was not associated with increased postoperative insulin requirement among patients with no diabetes undergoing TPIAT (odds ratio, 0.85; 95% confidence interval, 0.39-1.83; P = 0.67). CONCLUSIONS: Antecedent ERCP does not appear to have a deleterious impact on islet cell yield during TPIAT. Additional multicenter data are needed to more clearly determine the impact of ERCP in this context.